Pathophysiology of Diabetic Nephropathy

Sherril Sego


n the developed and industrialized world, diabetes is the leading cause of chronic kidney disease and kidney failure and the numbers of cases are increasing rapidly (Centers for Disease Control [CDC], 2005). Of the new end stage renal disease (ESRD) cases annually in the United States, about 44% are due to diabetes (United States Renal Data System [USRDS], 2007). With type 2 diabetes mellitus prevalence skyrocketing to over 21 million cases in the United States alone (CDC, 2005), catastrophic end organ diseases such as kidney failure will follow. Diabetic nephropathy, or kidney damage due to diabetes, results from changes in blood flow in the small vessels of the glomerular capsule, the functional unit of the kidney (Eknoyan et al., 2003). Each of the approximately 2 million glomerular capsules is composed of thin-walled capillaries that facilitate hydrostatic filtration of toxins and fluid and maintain a delicate balance of vasoconstriction and dilation (Hall, 2006). The pathogenic changes of diabetic nephropathy involve several different complex chains of reactions that culminate in damaging, oxidative remodeling of the vessel walls of the glomerular capsule. The subsequent decreased flow of oxygenated blood, loss of vasodilatory tone, and impairment of vascular wall integrity lead to irreversible damage to glomerular capillaries and, ultimately, to loss of kidney function (see Table 1).

Diabetic nephropathy is the primary etiology of chronic kidney disease and kidney failure. With the incidence of type 2 diabetes rapidly increasing in the United States, it is imperative for health care professionals to clearly understand the mechanism of this condition and the implications for prevention. Early recognition of the diabetic state and tight serum glucose control can help prevent the consequence of diabetic nephropathy and its associated life-altering comorbidities.

Table 1 Steps To Diabetic Nephropathy
1. 2. 3. 4. 5. 6. Hyperglycemia Thickening mesangium Glomerular hyperfiltration Impaired endothelial integrity Onset of microalbuminuria Impairment of nitric oxide transport 7. Loss of afferent/efferent auto-regulatory control 8. Continued loss of glomerular filtration capabilities

Pathophysiology of Diabetic Nephropathy
Diabetic nephropathy is characterized by the abnormal deposition of matrix material in the glomerular mesangium, leading to a thickened, sclerotic glomerular lining (Hall, 2006). Studies have shown that glucose reacts with proteins in the blood,
Sherril Sego, MSN, FNP-C, is Primary Care Nurse Practitioner, Kansas City VA Medical Center, Kansas City, MO.

chemically forming permanent crosslinked protein complexes (Makita et al., 1991). The excessive accumulation of these complexes, or advanced glycosylated end products (AGEs) is believed to directly accelerate the vascular complications of diabetes (Makita et al., 1991). Years of continued hyperglycemia and dyslipidemia, often in the presence of hypertension, promote the deposition of an accumulating layer of AGEs (Makita et al., 1991). The arterial microvascular structure consists of a five-layer vessel wall (Stam et al., 2006). These layers, much like an automobile tire, are wrapped and bonded to form an intricate system of support and function. The intima, or innermost wrapping, consists of a layer of endothelial cells, or endothelium. The endothelium is responsible for vascular tone, regulation of leukocyte and platelet adhesion, and controlling permeability to proteins and nitric oxide (Stam et al., 2006). Especially important to note is the function of nitric oxide in the microvasculature. It is a potent endothelial-derived vasodilator that participates in maintaining the normal

endovascular pressure. Also known as ‘endothelium-derived relaxing factor,’ nitric oxide functions as a signaling molecule in a complex chain of events. Manufactured in the endothelium from arginine and oxygen via an enzyme system, nitric oxide is an unstable free radical that “signals” the smooth muscle band of the vessel wall to relax, thus producing vasodilatation and increased blood flow (Tuteja, Chandra, Tuteja, & Misra, 2004). The endothelium is the layer that becomes most damaged by the long-term effects of hyperglycemia (Stam et al., 2006). As elevated glucose levels persist with subsequent formations of AGEs, the endothelium gradually thickens, loses its permeability to nitric oxide and becomes subject to increased platelet and leukocyte adhesion. As this adhesive layer thickens, once tightly controlled transport pores become stiff and open, leading to leakage of serum proteins from the vasculature (Stam et al., 2006). First described by Brownlee, Vlassara and Cerami (1984), this process of AGE formation is defined as the covalent bonding, or, glycosylation, of glucose to red blood cells. In the formation of AGEs, excess serum glucose combines with serum or tissue proteins, eventually forming an irreversible collagen-like complex. As these protein-collagen complexes deposit on the ever-thickening vascular wall, they accelerate endothelial dysfunction (Brownlee et al., 1984). It has been suggested that the thickening accumulation of these circulating end products within the vascular wall might serve as a trap for even more undesirable circulating molecules such as immunoglobulins and lipoproteins (Brownlee et al., 1984).


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outcomes for health prevention and promotion continue. The patient must believe he/she is personally at risk for this disease or condition. early intervention in the management of hyperglycemia has been shown to halt the progression of glomerular damage and stabilize kidney function (National Diabetes Information Clearinghouse [NDIC].). after all these. Conversely. [UKPDS]. The patient must be willing to invest himself/herself in the effort of implementing the proposed treatment. As devastating as this condition is. Access to internet sites and numerous patient education tools put endless resources at the fingertips of all nursing staff and most patients. Cost-effective ways of measuring serum concentrations of AGEs in the clinical setting are being sought so that by monitoring AGE amounts. The link between uncontrolled hyperglycemia and the development of vascular complications has been well established (Odetti et al. eventually leads to thickening of the glomerular basement membrane and loss of selective permeability (Parmer. 3. support. As endothelial damage progresses the intimal integrity is impaired. that is especially true. In a review of the Health Belief Model. gross albuminuria. 1998). The extent of this protein/collagen cross linking is directly related to the degree and duration of hyperglycemia (Odetti et al. The patient must internalize that this disease will have a severe impact on his/her life. In the case of diabetic nephropathy. No. 2001). Basic education on diabetes should be done for all patients and reinforced at every possible opportunity. and further accumulation of toxic products. Though the normal system constantly produces AGEs. albuminuria. constant support and education are essential. 2001). Though micro-vascular damage is irreversible. Kanauchi and colleagues devised a laboratory assay that validates the proportionate decrease in glomerular filtration rate with the increase in free-circulating AGEs. Now. A clear understanding of medications. Implications for Nursing Practice Kidney failure is quite possibly the most patient-education intensive field for nursing today. 2003). 2. and basic anatomy and physiology equip the patient to deal with their disease effectively. End-stage kidney failure is typically characterized by a glomerular filtration rate (GFR) of 10% or less. This elevated intraglomerular pressure stimulates several responses within the glomerular capillary bed. 1984). but the concomitant rise in serum creatinine is measured as well (Zilin et al. 2003). Microalbuminuria develops as well as impairment of nitric oxide transport (Eknoyan et al. not only the AGE level is measured. 2001).. nurses are the primary health care providers that develop patient relationships and ongoing interactions. Whether in hospitals or outpatient settings. 2006).. This. the concentration of advanced glycosylated end products is inversely proportionate to the glomerular filtration rate (Odetti et al. Endothelial mesangial cells thicken (Parmer. 2002). laboratory values. This testing process involves a flow injection assay (FIA) to produce a high performance liquid chromatography (HPLC) that detects the relatively low molecular mass of AGEs (Zilin. 2006). and encouragement.. With the scope of this disease involving every aspect of the patient’s life... no single factor is considered as capable of influencing patients’ decisions and compliance as that of a trusting relationship with the health care provider.. It is easy to see that this becomes a vicious cycle of AGE production and deposition. 34. Jones. together with the continual deposition of AGEs. begins (Brownlee et al. 1998). Initially. an increase in glomerular filtration pressure develops (Parmer. diet. to be dismal.3 ml/year decline in glomerular filtration rate (United Kingdom Prospective Diabetes Study. As with most diseases. Bicheng & Jiping. Patients look to the nurse for information. Uremia in diabetic nephropathy is associated with both an increased serum level of AGEs and accelerated micro and macrovascular angiopathy (Friedman. Tsujimoto. n. Tight glucose control normalizes the production of AGEs and stabilizes kidney AGE excretion so intimal deposition is prevented (Hall. 6 . This test. early signs of nephropathy might be predicted sooner than with current methods (Kanauchi.. Naifeng. the best way to manage the problem is to prevent it from happening. is far from being available in general medical reference laboratories. at glycosylated hemoglobin level of 8. 1998).7 +/. In this case. or protein loss. 4.2. However. decreased kidney excretion. The typical diabetic co-morbidities of hypertension and hyperlipidemia accelerate the destruction of the vascular wall integrity.0% there is a 1. 2002). however. The first appearance of microalbuminuria (urine albumin level greater than 50 mg/L) can precede end stage damage by as much as 20 years (Eknoyan et al. 2002). Though much research has been done exploring what factors influence patient compliance with health care regimens.d. 1998). Normally excreted by the kidney. 1984). due to an impairment of the afferent arteriolar autoregulatory ability. The patient must believe that the treatments recommended for him/her by medical professionals will actually help the problem. Jones. 2002). in many cases.Pathophysiology of Diabetic Nephropathy Kidney function depends on the intact function of the intricate glomerular micro-vasculature (Brownlee et al.. and elevated blood urea nitrogen/creatinine levels (Parmer. 1988). & Hashimoto. that provider is the nurse ( Jones et al.. the rate of progression to this level of severity is actually very gradual. Data confirms that for every 1% reduction in glycosylated hemoglobin there is a 37%-40% reduction in renal failure risk (Hall. vascular injury and dysfunction. and Katz (1988) cite several factors that determine patient compliance: 1. 1999). We now realize that many cases of type 2 diabetes can be prevented 632 NEPHROLOGY NURSING JOURNAL ■ November-December 2007 ■ Vol. this continuous process is magnified by high ambient glucose concentrations.

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